Abstract
Neuroprotective proteins expressed in the fetus play a critical role during early embryonic neurodevelopment, especially during maternal exposure to alcohol and drugs that cause stress, glutamate neuroexcitotoxicity, and damage to the fetal brain, if prolonged. We have identified a novel protein, carboxypeptidase E-ΔN (CPE-ΔN), which is a splice variant of CPE that has neuroprotective effects on embryonic neurons. CPE-ΔN is transiently expressed in mouse embryos from embryonic day 5.5 to postnatal day 1. It is expressed in embryonic neurons, but not in 3 week or older mouse brains, suggesting a function primarily in utero. CPE-ΔN expression was up-regulated in embryonic hippocampal neurons in response to dexamethasone treatment. CPE-ΔN transduced into rat embryonic cortical and hippocampal neurons protected them from glutamate- and H2O2-induced cell death. When transduced into embryonic cortical neurons, CPE-ΔN was found in the nucleus and enhanced the transcription of FGF2 mRNA. Embryonic cortical neurons challenged with glutamate resulted in attenuated FGF2 levels and cell death, but CPE-ΔN transduced neurons treated in the same manner showed increased FGF2 expression and normal viability. This neuroprotective effect of CPE-ΔN was mediated by secreted FGF2. Through receptor signaling, FGF2 activated the AKT and ERK signaling pathways, which in turn increased BCL-2 expression. This led to inhibition of caspase-3 activity and cell survival.
Highlights
Glutamate release is required for normal fetal neurodevelopment, but excess release leads to neuronal damage and neuropathogenesis
carboxypeptidase E-DN (CPE-DN) mRNA was detected at E5.5 and the amount doubled at E8.5
We have identified the splice variant of carboxypeptidase E (CPE), CPE-DN, as a new neuroprotective protein that likely plays an important role during embryonic development
Summary
Glutamate release is required for normal fetal neurodevelopment, but excess release leads to neuronal damage and neuropathogenesis. Various conditions such as maternal acute alcohol exposure in vivo [1], maternal hemorrhage [2] or maternal chronic hypoxemia [3], results in increased glutamate release from the fetal cortex leading to neuronal cell death. Endogenous neuroprotective factors exist in the fetal brain to maintain neuronal survival and prevent onset of and is more visible in the CPE-DN-transduced vs control cells. C. Bar graphs show an increase in CPE-DN mRNA expression in rat E18 hippocampal neurons treated with dexamethasone compared to control untreated neurons. Values are the mean ¡SEM (n54). t test *** p,0.001
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